Cocaine addiction is a complex phenotype resulting from an interaction from genetic and environmental factors. The overall-arching rationale for this proposal is that specific polygenetic backgrounds interact with specific experiences to determine cocaine responsiveness making an individual more or less vulnerable to cocaine addiction. Our goal is to elucidate genetic factors that modulate the ability of early environmental experiences to alter adult responsiveness to cocaine. Extensive research has focused on delineating specific early (as well as adult) environmental conditions that increase cocaine responsiveness. Epidemiological data indicates broad-spectrum increases in neuropsychiatric disease for that are in utero during natural and man- made disaster. In animal studies, prenatal stress produces an adult phenotype comprising increased sensitivity to psychomotor stimulant effects of cocaine, greater cocaine intake during cocaine self-administration, and higher cocaine-seeking during extinction and reinstatement procedures suggesting that a history of early life stress produce greater vulnerability to cocaine addiction. Conversely, extensive research has also focused on determining which gene variants increase cocaine responsiveness. Clinical and familial studies indicate a substantial inheritance to cocaine addiction with minimal estimates indicating genetic variability can account for 30% of variability in addiction vulnerability across individuals. In animal studies, substantial differences between mouse strains have been observed in the behavioral and physiological effects of cocaine. Further, the mapping of the mouse genome along with the construction recombinant inbred mouse strain panels now allows quantitative analyses of the contribution of specific genetic loci to cocaine responsiveness. Conversely there is emerging evidence for gene-environment interactions in determining cocaine responsiveness, and, currently, a major impediment to our ability to predict individual cocaine responsiveness is the lack of systematic investigation of the interactions between genes and environment and determination of these factors will facilitate a priori determination of individuals at risk for cocaine addiction. Thus, it is now time to extend quantitative trait loci analyses by incorporating systematic investigation of gene-environment interactions, for e.g. determination of the specific genetic loci genes that facilitate or impede early environmental modulation of cocaine responsiveness. The overall goal of the present proposal is to provide an analysis of the early environmental modulation of genetic predisposition to addiction vulnerability employing a mouse model. Aim 1 will assess prenatal stress (PNS)-induced differences in cocaine responsiveness between two mouse strains that show distinct cocaine responsiveness (C57BL/6 and DABA/2J) and their F1 progeny. This will include assessment of strain x PNS shifts in the dose-response curve for not only the psychostimulant, but also the rewarding, properties of cocaine as well as responsiveness to mild psychological and physical stressors and neuroadaptations in these responses with repeated exposures. In order to more directly investigate the interaction between specific genetic factors (at the chromosomal loci level) and early environmental stress, Aim 2 will examine the impact of PNS on cocaine responsiveness in across a panel of recombinant inbred strains derived from C57BL/6 and DBA/2 parental lines followed by quantitative trait loci (QTL) analyses to allow determination which specific chromosomal loci are associated with PNS-induced changes in cocaine responsiveness. In addition, control data for these responses will be utilized to replicate and extend previous RI-QTL studies. Finally, multivariant analyses will be performed on the genetic and phenotypic variables in order to determine inter-relatedness of these variables in attempt to define cluster factors that control cocaine responsiveness. These studies will provide novel analyses of gene-environment interactions by determining the specific genetic mediators of PNS-induced changes in cocaine responsiveness.